Targeting hypoxia signaling pathways in angiogenesis

Abstract

Oxygen (O₂) supply is constantly maintained by the vascular network for a proper tissue oxygenation. Hypoxia is the result of an increased O₂ demand and/or decreased supply and is common in both physiological conditions and human diseases. Angiogenesis is one of the adaptive responses to hypoxia and is mainly regulated by the hypoxia-inducible factors, HIFs. These heterodimeric transcription factors are composed of one of three O₂-dependent α subunits (HIF-1, HIF-2, and HIF-3) and a constitutively expressed O₂-insensitive subunit (HIF-1β). Among them HIF-1α is the most characterized and its activity is tightly controlled. Under hypoxia, its intracellular accumulation triggers the transcription of several genes, involved in cell survival/proliferation, autophagy, apoptosis, cell metabolism, and angiogenesis. HIF pathway is also modulated by specific microRNAs (miRNAs), thus resulting in the variation of several cellular responses, including alteration of the angiogenic process. The pro-angiogenic activity of HIF-1α is not restricted to endothelial cells, as it also affects the behavior of other cell types, including tumor and inflammatory/immune cells. In this context, exosomes play a crucial role in cell-cell communication by transferring bio-active cargos such as mRNAs, miRNAs, and proteins (e.g., VEGFA mRNA, miR210, HIF-1α). This minireview will provide a synopsis of the multiple factors able to modulate hypoxia-induced angiogenesis especially in the tumor microenvironment context. Targeting hypoxia signaling pathways by up-to-date approaches may be relevant in the design of therapeutic strategies in those pathologies where angiogenesis is dysregulated.

Keywords: HIFs; angiogenesis; endothelial cells; exosomes; hypoxia; immune cells; miRNAs.

FIGURE 1

Hypoxia-inducible factors (HIFs) signaling pathway. Under normoxic conditions, HIF1/2 are hydroxylated by prolyl hydroxylase domain (PHD)-containing enzymes. Hydroxylated HIFs are degraded in the proteasomes by von Hippel-Lindau tumor suppressor protein (VHL) via polyubiquitination. During hypoxic conditions, PHDs and FIH are inhibited and HIF-α subunits are translocated into the nucleus, where can dimerize with HIF1-β, recruit p300 and CBP, and ultimately, bind to HREs at target genes to cause activation.

FIGURE 2

HIF-1/2α and angiogenesis. Along with hypoxia, several mediators, including exosomes, miRNAs and immune cells, are involved in angiogenesis modulation by affecting directly or indirectly HIF-1/2α.